rs145847114

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017636.4(TRPM4):c.2209G>A(p.Gly737Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,062 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G737A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 19 hom. )

Consequence

TRPM4
NM_017636.4 missense, splice_region

Scores

Splicing: ADA: 0.00004656

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.841

Publications

10 publications found

Variant links:

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

TRPM4 Gene-Disease associations (from GenCC):

erythrokeratodermia variabilis et progressiva 6
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
progressive familial heart block type IB
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
erythrokeratodermia variabilis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
progressive familial heart block
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

TRPM4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_017636.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069471).

BP6

Variant 19-49190772-G-A is Benign according to our data. Variant chr19-49190772-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468934.

BS2

High AC in GnomAd4 at 286 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017636.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM4	NM_017636.4	MANE Select	c.2209G>A	p.Gly737Arg	missense splice_region	Exon 16 of 25	NP_060106.2
TRPM4	NM_001321281.2		c.1864G>A	p.Gly622Arg	missense splice_region	Exon 14 of 23	NP_001308210.1
TRPM4	NM_001195227.2		c.2209G>A	p.Gly737Arg	missense splice_region	Exon 16 of 24	NP_001182156.1	Q8TD43-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.2209G>A	p.Gly737Arg	missense splice_region	Exon 16 of 25	ENSP00000252826.4	Q8TD43-1
TRPM4	ENST00000427978.6	TSL:1	c.2209G>A	p.Gly737Arg	missense splice_region	Exon 16 of 24	ENSP00000407492.1	Q8TD43-3
TRPM4	ENST00000595519.5	TSL:1	n.*1619G>A		splice_region non_coding_transcript_exon	Exon 14 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

287

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00203

AC:

510

AN:

251400

AF XY:

0.00232

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00184

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00191

AC:

2795

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1517

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.00159

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00734

AC:

633

AN:

86246

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00798

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00165

AC:

1832

AN:

1111958

Other (OTH)

AF:

0.00225

AC:

136

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

137

275

412

550

687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152256

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41542

American (AMR)

AF:

0.00451

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00808

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00200

AC:

136

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00196

Hom.:

Bravo

AF:

0.00174

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00245

EpiControl

AF:

0.00249

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Progressive familial heart block type IB (2)

Cardiovascular phenotype (1)

Hypertrophic cardiomyopathy (1)

TRPM4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.18

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.11

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.2

PhyloP100

-0.84

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.86

REVEL

Benign

0.052

Sift

Benign

0.35

Sift4G

Benign

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.29

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000047

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over